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中等剂量低分子肝素不能降低有静脉血栓栓塞史孕产妇的复发风险
作者:小柯机器人 发布时间:2022/10/31 10:42:33

近日,荷兰拉德堡德大学医学中心Saskia Middeldorp团队比较了中等剂量与低剂量低分子肝素对有静脉血栓栓塞史的孕妇和产后妇女复发的影响。该研究于2022年10月28日发表在《柳叶刀》杂志上。

妊娠相关静脉血栓栓塞是产妇发病率和死亡率的主要原因,有静脉血栓栓塞病史的孕妇和产后妇女应采取血栓预防措施。低分子肝素预防妊娠期和产后静脉血栓栓塞复发的最佳剂量尚不确定。

在这项开放标签、随机、对照试验中,研究组从9个国家(荷兰、法国、爱尔兰、比利时、挪威、丹麦、加拿大、美国和俄罗斯)的70家医院招募有静脉血栓栓塞史的孕妇,若女性年龄在18岁及以上,有客观证实的静脉血栓栓塞病史,且胎龄在14周或以下,则符合条件。符合条件的女性在孕龄14周前,使用基于网络的系统和置换块随机分组,按中心分层,以1:1随机分配接受按体重调整的中等剂量或固定的低分子量肝素,每天皮下注射一次,直到产后6周。

主要疗效结局是在意向治疗(ITT)人群(即随机分配给治疗的所有女性)中,由独立中央评审委员会确定的客观证实的静脉血栓栓塞(即深静脉血栓、肺栓塞或异常部位静脉血栓)。主要安全性结局为大出血,包括产前、产后早期(产后24小时内)和产后晚期大出血(产后24 h或更长时间,直至产后6周),对所有接受至少一剂指定治疗且已知治疗结束日期的女性进行了评估。

2013年4月24日至2020年10月31日,研究组对1339名孕妇进行了资格筛选,其中1110名孕妇被随机分配接受按体重调整中等剂量(n=555)或固定低剂量(n=555)低分子肝素(ITT人群)。体重调整中等剂量组的555名女性中有11名(2%)发生静脉血栓栓塞,固定低剂量组的555名女性中有16名(3%),相对风险(RR)为0.69。

中等剂量组有5名(1%)女性在产前发生静脉血栓栓塞,低剂量组有5名(1%);中等剂量组有6名(1%)女性在产后发生静脉血栓栓塞,低剂量组有11名(2%)。治疗期间,中等剂量组520名女性中有23名(4%)发生了安全人群(N=1045)的大出血,低剂量组525名女性中有20名(4%),RR为1.16。

研究结果表明,在有静脉血栓栓塞病史的女性中,在产前和产后合并期间,体重调整的中等剂量低分子肝素与固定低剂量低分子肝素相比,并不能降低复发风险。

附:英文原文

Title: Intermediate-dose versus low-dose low-molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study): an open-label, multicentre, randomised, controlled trial

Author: Ingrid M Bistervels, Andrea Buchmüller, Hanke M G Wiegers, Fionnuala Ní áinle, Bernard Tardy, Jennifer Donnelly, Peter Verhamme, Anne F Jacobsen, Anette T Hansen, Marc A Rodger, Maria T DeSancho, Roman G Shmakov, Nick van Es, Martin H Prins, Céline Chauleur, Saskia Middeldorp, Eline S van den Akker, Mireille N Bekker, Thomas van Bemmel, Laurent Bertoletti, Julie Blanc, Suzanne M Bleker, Aude Bourtembourg-Matras, Florence Bretelle, Bridgette Byrne, Francis Couturaud, Pierre Delorme, Elise S Eerenberg, Maureen TM Franssen, Jens Fuglsang, Wessel Ganzevoort, Franois Goffinet, Jiska M de Haan-Jebbink, Wieteke Heidema, Monique A Hertzberg, Marcel MC Hovens, Menno V Huisman, Leonie de Jong-Speksnijder, Pieter-Willem Kamphuisen, Denis J OKeeffe, Karine Lacut, Josje Langenveld, M Simone Lunshof, Caroline P Martens, Adel Merah, Emmanuelle Le Moigne, Dimitri NM Papatsonis, Gilles Pernod, Franck Perrotin, Edith Peynaud-Debayle, Fabrice Pierre, Geneviève Plu Bureau, Tiphaine Raia-Barjat, Robbert JP Rijnders, Roger Rosario, Marc Ruivard, Jeannot Schmidt, Marieke Sueters, Thomas Vanassche, Marie-Nolle Varlet, Alexandre J Vivanti, Matthieu Y van der Vlist, Lucet F van der Voet, Karlijn C Vollebregt, Johanna IP de Vries, Sabina de Weerd, Peter E Westerweel, Lia DE Wijnberger, Marije ten Wolde, Paula F Ypma, Catherine Zuily-Lamy, Joost J Zwart, Alexandra Benachi, Gal Beucher, Holy Bezanahary, Karin de Boer, Marjon A. de Boer, Frantz Bousquet, Henk A. Bremer, Luc Bressollette, Aurélie Brossard, Cécile Chau, Brian Cleary, Fabienne Comte, Thomas Corsini, Anne Coustel, Barbara Debaveye, Raoul Desbrière, Cécile Duvillard, Astrid Eckman, Jeroen Eikenboom, Antoine Elias, Laura M. Faber, Emile Ferrari, Denis Gallot, Emilie Gauchotte, Ingrid Gaugler, Abby E. Geerlings, Audrey OGorman, Vincent Grobost, Pieter-Kees de Groot, David P. van der Ham, Brenda Hermsen, Kim Kamphorst, Alan Karovitch, Gunilla Kleiverda, Aiste Kloster, Annemarieke Koops, Inneke Krabbendam, Marieke J.H.A. Kruip, Saskia Kuipers, Judith van Laar, Damien Laneelle, Suzanne Lima, Peter MacMahon, Laurent Mandelbrot, Claudia A. van Meir, Caroline Menez, Leonard P. Morssink, Nathalie Moulin, Eve Mousty, Matthieu Muller, Lucy Murphy, Kathelijne Peerlinck, Alma OReilly

Issue&Volume: 2022-10-28

Abstract:

Background

Pregnancy-related venous thromboembolism is a leading cause of maternal morbidity and mortality, and thromboprophylaxis is indicated in pregnant and post-partum women with a history of venous thromboembolism. The optimal dose of low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy and the post-partum period is uncertain.

Methods

In this open-label, randomised, controlled trial (Highlow), pregnant women with a history of venous thromboembolism were recruited from 70 hospitals in nine countries (the Netherlands, France, Ireland, Belgium, Norway, Denmark, Canada, the USA, and Russia). Women were eligible if they were aged 18 years or older with a history of objectively confirmed venous thromboembolism, and with a gestational age of 14 weeks or less. Eligible women were randomly assigned (1:1), before 14 weeks of gestational age, using a web-based system and permuted block randomisation (block size of six), stratified by centre, to either weight-adjusted intermediate-dose or fixed low-dose low-molecular-weight heparin subcutaneously once daily until 6 weeks post partum. The primary efficacy outcome was objectively confirmed venous thromboembolism (ie, deep-vein thrombosis, pulmonary embolism, or unusual site venous thrombosis), as determined by an independent central adjudication committee, in the intention-to-treat (ITT) population (ie, all women randomly assigned to treatment). The primary safety outcome was major bleeding which included antepartum, early post-partum (within 24 h after delivery), and late post-partum major bleeding (24 h or longer after delivery until 6 weeks post partum), assessed in all women who received at least one dose of assigned treatment and had a known end of treatment date. This study is registered with ClinicalTrials.gov, NCT01828697, and is now complete.

Findings

Between April 24, 2013, and Oct 31, 2020, 1339 pregnant women were screened for eligibility, of whom 1110 were randomly assigned to weight-adjusted intermediate-dose (n=555) or fixed low-dose (n=555) low-molecular-weight heparin (ITT population). Venous thromboembolism occurred in 11 (2%) of 555 women in the weight-adjusted intermediate-dose group and in 16 (3%) of 555 in the fixed low-dose group (relative risk [RR] 0·69 [95% CI 0·32–1·47]; p=0·33). Venous thromboembolism occurred antepartum in five (1%) women in the intermediate-dose group and in five (1%) women in the low-dose group, and post partum in six (1%) women and 11 (2%) women. On-treatment major bleeding in the safety population (N=1045) occurred in 23 (4%) of 520 women in the intermediate-dose group and in 20 (4%) of 525 in the low-dose group (RR 1·16 [95% CI 0·65–2·09]).

Interpretation

In women with a history of venous thromboembolism, weight-adjusted intermediate-dose low-molecular-weight heparin during the combined antepartum and post-partum periods was not associated with a lower risk of recurrence than fixed low-dose low-molecular-weight heparin. These results indicate that low-dose low-molecular-weight heparin for thromboprophylaxis during pregnancy is the appropriate dose for the prevention of pregnancy-related recurrent venous thromboembolism.

DOI: 10.1016/S0140-6736(22)02128-6

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)02128-6/fulltext

期刊信息

LANCET:《柳叶刀》,创刊于1823年。隶属于爱思唯尔出版社,最新IF:59.102
官方网址:http://www.thelancet.com/
投稿链接:http://ees.elsevier.com/thelancet